The E3 ubiquitin ligase itch couples JNK activation to TNFα-induced cell death by inducing c-FLIPL turnover
The E3 ubiquitin ligase itch couples JNK activation to TNFα-induced cell death by inducing c-FLIPL turnover
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DOI：
10.1016/j.cell.2006.01.021
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发表时间：
2006-02-10
期刊：
影响因子：
64.5
通讯作者：
Karin, M
中科院分区：
文献类型：
--
作者：
Chang, LF;Kamata, H;Karin, M
促炎细胞因子肿瘤坏死因子（TNF）α信号细胞存活和死亡。TNF α治疗的生物学结果由NF-κ B和Jun激酶（JNK）信号传导之间的平衡决定; NF-κ B促进存活，而JNK增强细胞死亡。重要的是，促进TNF α诱导的细胞凋亡的JNK底物的身份是突出的。在这里，我们表明，TNF α介导的JNK激活加速营业额的NF-κ B诱导的抗凋亡蛋白c-FLIP，caspase-8的抑制剂。这不是由于直接的c-FLIP磷酸化，而是依赖于JNK介导的磷酸化和E3泛素连接酶Itch的活化，其特异性地泛素化c-FLIP并诱导其蛋白酶体降解。JNK 1或瘙痒缺陷或用JNK抑制剂治疗使小鼠在TNF α诱导的急性肝衰竭的三种不同模型中具有抗性，并且来自这些小鼠的细胞不显示可诱导的c-FLIPL泛素化和降解。因此，JNK通过促进c-FLIPL的蛋白酶体消除来拮抗TNF α信号传导过程中的NF-κ B。
The proinflammatory cytokine tumor necrosis factor (TNF) alpha signals both cell survival and death. The biological outcome of TNF alpha treatment is determined by the balance between NF-kappa B and Jun kinase(JNK) signaling; NF-kappa B promotes survival, whereas JNK enhances cell death. Critically, identity of a JNK substrate that promotes TNF alpha-induced apoptosis has been outstanding. Here we show that TNF alpha-mediated JNK activation accelerates turnover of the NF-kappa B-induced antiapoptotic protein c-FLIP, an inhibitor of caspase-8. This is not due to direct c-FLIP phosphorylation but depends on JNK-mediated phosphorylation and activation of the E3 ubiquitin ligase Itch, which specifically ubiquitinates c-FLIP and induces its proteasomal degradation. JNK1 or Itch deficiency or treatment with a JNK in hi bitor renders mice resistant in three distinct models of TNFa-induced acute liver failure, and cells from these mice do not display inducible c-FLIPL ubiquitination and degradation. Thus, JNK antagonizes NF-kappa B during TNF alpha signaling by promoting the proteasomal elimination of c-FLIPL.